Researchers identify
process that starts skin aging

By Sally PobojewskiMedical
Center Public Relations

U-M scientists have identified a biochemical
process, that, when triggered by ultraviolet radiation in sunlight, leads
to premature skin aging. The study, published in the Nov. 13 issue of the
New England Journal of Medicine, shows that surprisingly small
amounts of exposure to sunlight are enough to start the premature aging
process.

"From a public health standpoint, the major significance of
this study is the evidence indicating that exposure to a few minutes of
sunlight periodically over several years can lead to premature skin
aging," says John J. Voorhees, the Duncan O. and Ella M. Poth
Distinguished Professor of Dermatology and the study's senior author.
"This is far less than the exposure required to produce any visible
reddening of the skin."

"Although sunscreens help prevent skin cancer
and sunburn, they may not protect against skin photoaging, since it
appears that sunburn and photoaging may be caused by different kinds of
ultraviolet sunlight," says Gary J. Fisher, associate research scientist
in dermatology and the study's lead author.

"New sunscreens and drugs
may need to be developed to combat premature aging. We found that
pretreating skin with retinoic acid-the business end of vitamin A or
retinol-before UV exposure inhibited the biochemical changes leading to
premature skin aging."

Major points in the article included:

Repeated exposure to ultraviolet radiation in sunlight causes skin
to age prematurely-a condition called photoaging. Photoaged skin has
wrinkles, brown spots, changes in pigmentation and surface roughness.
These skin changes are not part of the natural, normal aging process.

The most likely cause for the visible wrinkling associated with
photoaging is the breakdown of collagen-the major structural material in
skin. Ninety-five percent of the dermis, or underlying layer of skin, is
made of collagen.

Ultraviolet radiation in sunlight triggers a
molecular chain reaction which produces large amounts of enzymes called
matrix metalloproteinases (MMPs). MMPs break apart and degrade collagen.
While skin has a natural ability to repair damaged collagen, these repairs
are never perfect.

Tiny amounts of at first invisible scar tissue build
up over time and eventually become visible as wrinkles (photoaging).

U-M scientists found that MMP levels in dermal skin were directly
associated with the length and frequency of exposure to ultraviolet light.
Exposure to small amounts of UV (too small to cause skin redness) every
other day was enough to induce sustained MMP production at high levels in
the individuals in this study.

Pretreating skin with retinoic acid
before UV exposure inhibited production of MMPs and resulting collagen
damage by 70 to 80 percent in the U-M study. Because it blocks MMP
production, retinoic acid should also prevent photoaging, although more
research will be needed to know for sure.

The possibility of
photoaging prevention is a surprising outcome of this study. Retinoic
acid is already approved by the FDA to treat photoaging that has already
happened. But until now, the possibility that vitamin A and retinoic acid
might prevent photoaging has not been seriously considered.

While
retinoic acid blocks MMP production, it has no effect on the skin's
ability to produce enzymes called Tissue Inhibitors of MetalloProteinases
(TIMPs) which naturally prevent MMP-induced collagen damage. Retinoic
acid may prevent photoaging by reducing amounts of harmful enzymes in the
dermis, while maintaining normal levels of tissue-protecting proteins
(TIMPs).

Future research will attempt to discover how retinoic acid
blocks MMP activation when skin is exposed to ultraviolet light. U-M
scientists are exploring the role played by a protein called AP-1, which
"turns on" genes in skin cells causing them to produce both MMPs and
TIMPs.

In addition to Voorhees and Fisher, co-investigators on the
study were ZengQuan Wang, Subhash C. Datta, James Varani and Sewon Kang,
all from the Department of Dermatology.